Asthma, bronchitis and emphysema are known as Chronic Obstructive Pulmonary Diseases (COPD). COPD is characterized as generalized airway obstruction, particularly of small airways, associated with varying degrees of symptoms of chronic bronchitis, asthma, and emphysema. The term COPD was introduced because these conditions often coexist, and it may be difficult in an individual case to decide which is the major condition producing the obstruction. Airway obstruction is defined as an increased resistance to airflow during forced expiration. It may result from narrowing or restriction of an airway secondary to intrinsic airway disease, from excessive collapse of the airway during a forced expiration secondary to pulmonary emphysema, from bronchospasm as in asthma, or may be due to a combination of these factors. Although obstruction of large airways may occur in all these disorders, particularly in asthma, patients with severe COPD characteristically have major abnormalities in their small airways, namely those less than 2 mm internal diameter, and much of the obstruction of their airway is situated in this zone. The airway obstruction is irreversible except for that which can be ascribed to asthma.
Asthma is a reversible obstructive respiratory disorder characterized by increased responsiveness of the airway. Asthma can occur secondarily to a variety of stimuli. The underlying mechanisms are unknown, but inherited or acquired imbalance of adrenergic and cholinergic control of airway diameter has been implicated. Asthmatics manifesting such imbalance have hyperactive bronchi and, even without symptoms, bronchoconstriction may be present. Overt asthma attacks may occur when such individuals are subjected to various stresses, such as viral respiratory infection, exercise, emotional upset, nonspecific factors (e.g., changes in barometric pressure or temperature), inhalation of cold air or irritants (e.g., gasoline fumes, fresh paint and noxious odors, or cigarette smoke), exposure to specific allergens, and ingestion of aspirin or sulfites in sensitive individuals. Those whose asthma is precipitated by allergens (most commonly airborne pollens and molds, house dust, animal danders) and whose symptoms are IgE-mediated are said to have allergic or "extrinsic" asthma. They account for about 10 to 20% of adult asthmatics; in another 30 to 50%, symptomatic episodes seem to be triggered by non-allergenic factors (e.g., infection, irritants, emotional factors), and these patients are said to have nonallergic or "intrinsic" asthma. In many persons, both allergenic and non-allergenic factors are significant.
Racemic salmeterol is a .beta..sub.2 adrenoceptor-selective sympathomimetic, whose primary use is as a long-acting bronchodilator for the prevention of bronchospasm in patients with obstructive airway disease such as asthma, bronchitis and emphysema.
Most of the .beta..sub.2 agonists cause somewhat similar adverse effects. These adverse effects include but are not limited to cardiovascular effects such as palpitations, increased heart rate, and tachycardia; central nervous system symptoms such as nervousness, dizziness, headache and drowsiness; respiratory side effects such as dyspnea, wheezing, drying or irritation of the oropharynx, coughing, chest pain and chest discomfort; hand tremors, muscle tremors, and immediate hypersensitivity reactions such as urticaria, angioedema, rash and even bronchospasms.
Furthermore, patients have a tendency to develop a tolerance to the bronchodilating effect of .beta..sub.2 agonists. This is related to desensitization, which is one of the most clinically significant phenomena involving the .beta.-adrenergic receptor. It has been observed that patients in prolonged .beta.-agonist therapy have a tendency to increase the dosage of drug they use. This occurs because after prolonged administration, the .beta. receptor appears to become desensitized to the agonist, thus requiring larger doses of the compound to effect an equivalent physiological response.
The problem of desensitization is especially significant in the treatment of diseases involving bronchospasms, such as asthma. The treatment of asthma usually involves the self-administration either orally or by aerosol, of .beta.-adrenergic agonists such as the racemic mixture of salmeterol. Asthmatic patients utilizing .beta.-agonists for a prolonged time gradually increase the self-administered dose in order to get a sufficient amount of bronchodilation and relief in breathing. As a result of this increased dosage, the agonist acts on the .beta. receptors of the heart and vasculature to cause cardiovascular stress and other adverse effects.
A general suggestion has been made in the literature that the (R) enantiomer is the .beta..sub.2 stimulatory enantiomer (eutomer) of most, if not all, phenethanolamine .beta..sub.2 adrenoceptor-selective sympathomimetics, and this general teaching has been applied to salmeterol. Thus U.S. Pat. No. 4,992,474 states that the compounds of the genus that includes salmeterol exist in enantiomeric forms and that compounds in which the alcohol carbon is in the R configuration are preferred. Similarly, Chapman et al. [Trends Pharmacol Sci 13, 231-232 (1992)] discussed the problem of chirality in .beta..sub.2 adrenoceptor-selective sympathomimetics, and concluded that agonist activity resides in the R enantiomer of isoprenaline, salbutamol, salmeterol and terbutaline. British Patent 2,255,503 discloses the use of a single enantiomer of various .beta..sub.2 adrenoceptor-selective sympathomimetics, including salmeterol, and indicates that, in the case of salmeterol the enantiomer to use to minimize side effects is the (R) enantiomer. As recently as 1996, those of skill in the art have continued to suggest that "The .beta. adrenoceptor activity of albuterol and other agonists [salmeterol is among those named] has been shown to reside mainly in the R-enantiomer (eutomer) with little or no adrenoceptor stimulation attributed to the S-enantiomer (distomer)." [Boulton and Fawcett Clin. Rev. Allergy Immunol. 14, 115-138 (1996)] Thus the present invention--the use of the S enantiomer--goes directly against the clear teachings of all of the known art.